It is often desired to replace or reconstruct all or a portion of a living bone, such as when a bone has been broken or has been resected as a result of a bone tumor. In these instances, the missing bone can be replaced with a mechanical device, such as a pin, plate or the like, or it can be replaced with an implant that is designed to more closely resemble the original bone itself. Often these implants comprise biodegradable compounds or parts made from such compounds. For example, it is known to provide porous, biodegradable compounds that contain or are coated with an osteogenic substance. It is contemplated that bone tissue will grow back into the pores of the implant and will gradually replace the entire implant as the implant itself is gradually degraded in the in vivo environment.
For obvious reasons, implants should be biocompatible and non-toxic. Furthermore, the steps required for implantation of the implant (eg. the application or generation of heat and the generation of chemical by-products) should also be biocompatible and non-toxic. For example, the generation of extreme heat or lethal temperatures can cause necrosis of the tissue surrounding the implant site. Also, the techniques and time periods required for implantation should be suited to the surgical environment.
Under current practices, bone implants are typically formed from a substance that is initially malleable and then becomes hard after a reasonably short period of time. The time required for the bone replacement compound to become fully cross-linked (i.e. its gel point) should be long enough to allow positioning and manipulation by the surgeon and short enough to ensure that the compound has hardened before surgery is complete. A desirable gel point is typically in the range of from about 1 minute to about 120 minutes and more preferably between about 5 and about 60 minutes. In addition, it is often desirable to be able to select or control the gel point, so that the gel point can be optimized for a given surgical situation.
In addition, because living bone tends to atrophy and degrade in the absence of compressive stress, it is important that the implant not become too hard. An implant whose compressive strength is too great (i.e. an implant that is too hard) will cause stress shielding of the surrounding bone. Stress shielding in turn weakens the surrounding bone and may ultimately result in catastrophic failure. Normal human trabecular bone has an average compressive strength of approximately 5 MPa and modulus of elasticity of approximately 50 MPa Conventional bone cements are formed of poly(methylmethacrylate) (PMMA) or poly(methylmethacrylate-co-styrene). The compressive strength of these bone cements is approximately 100 MPa. This is much higher than the mid-range for trabecular bone (5 MPa), and is of the same order of magnitude as the mid-range compressive strength for compact bone. The much greater compressive strength of prior art bone cements can lead to stress shielding and loss of adjacent bone. Other disadvantages of known bone cements include that they are not degradable, and continually accumulate fatigue damage as they are loaded, which sometimes leads to structural failure.
Hence, the suitability of a given substance for implantation as a bone replacement depends on its biocompatibility, set time, biodegradability and compression strength. Certain polymers have been found to be suitable in this regard.
Poly(propylene fumarate) (hereinafter "T(PF)") is one such substance. P(PF) is an unsaturated linear polyester that degrades in the presence of water into propylene glycol and fumaric acid, degradation products which are cleared from the human body by normal metabolic processes. Although P(PF) has been previously known, its routine, reproducible synthesis and the synthesis of high molecular weight forms and forms with low polydispersity indices have not previously been successfully accomplished. Because the fumarate double bonds in P(PF) are reactive and crosslink at low temperatures, it has potential to be an effective in situ polymerizable biomaterial. U.S. Pat. No. 5,733,951 discloses a composite mixture incorporating P(PF), a crosslinking monomer (N-vinyl pyrrolidinone), a porogen (sodium chloride), and a particulate phase (.beta.-tricalcium phosphate) that can be injected or inserted into skeletal defects of irregular shape or size. The '951 patent does not disclose any method for controlling either gel time or the heat released during cross-linking. Hence, it is further desirable to provide a P(PF) composition wherein the heat released is minimized and the gel time is controllable, without adversely affecting the mechanical properties of the final product.